Cerebellar Cathodal Transcranial Direct Stimulation and Performance on a Verb Generation Task: A Replication Study

The role of the cerebellum in cognitive processing is increasingly recognized but still poorly understood. A recent study in this field applied cerebellar Transcranial Direct Current Stimulation (c-tDCS) to the right cerebellum to investigate the role of prefrontal-cerebellar loops in language aspects of cognition. Results showed that the improvement in participants' verbal response times on a verb generation task was facilitated immediately after cathodal c-tDCS, compared to anodal or sham c-tDCS. The primary aim of the present study is to replicate these findings and additionally to investigate possible longer term effects. A crossover within-subject design was used, comparing cathodal and sham c-tDCS. The experiment consisted of two visits with an interval of one week. Our results show no direct contribution of cathodal c-tDCS over the cerebellum to language task performance. However, one week later, the group receiving cathodal c-tDCS in the first visit show less improvement and increased variability in their verbal response times during the second visit, compared to the group receiving sham c-tDCS in the first visit. These findings suggest a potential negative effect of c-tDCS and warrant further investigation into long term effects of c-tDCS before undertaking clinical studies with poststroke patients with aphasia

Presupposition projection as proof construction

Even though Van der Sandt's presuppositions as anaphora approach is empirically successful, it fails to give a formal account of the interaction between world-knowledge and presuppositions. In this paper, an algorithm is sketched which is based on the idea of presuppositions as anaphora. It improves on this approach by employing a deductive system, Constructive Type Theory (CTT), to get a formal handle on the way world-knowledge influences presupposition projection. In CTT, proofs for expressions are explicitly represented as objects. These objects can be seen as a generalization of DRT's discourse markers. They are useful in dealing with presuppositional phenomena which require world-knowledge, such as Clark's bridging examples and Beaver's conditional presuppositions

Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273

BACKGROUND: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants. METHODS: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. RESULTS: OCR-treated MS patients exhibit a preserved recall response of CD8(+) T central memory cells following first vaccination compared to HCs and a similar CD4(+) circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4(+) and CD8(+) T cells. CONCLUSIONS: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8(+) T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients. FUNDING: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871)

Descriptions, truth value intuitions, and questions

International audienceSince the famous debate between Russell (Mind 14: 479–493, 1905, Mind 66: 385–389, 1957) and Strawson (Mind 59: 320–344, 1950; Introduction to logical theory, 1952; Theoria, 30: 96–118, 1964) linguistic intuitions about truth values have been considered notoriously unreliable as a guide to the semantics of definite descriptions. As a result, most existing semantic analyses of definites leave a large number of intuitions unexplained. In this paper, I explore the nature of the relationship between truth value intuitions and non-referring definites. Inspired by comments in Strawson (Introduction to logical theory, 1964), I argue that given certain systematic considerations, one can provide a structured explanation of conflicting intuitions. I show that the intuitions of falsity, which proponents of a Russellian analysis often appeal to, result from evaluating sentences in relation to specific questions in context. This is shown by developing a method for predicting when sentences containing non-referring definites elicit intuitions of falsity. My proposed analysis draws importantly on Roberts (in: Yoon & Kathol (eds.) OSU working papers in Linguistics: vol. 49: Papers in Semantics 1998; in: Horn & Ward (eds.) Handbook of pragmatics, 2004) and recent research in the semantics and pragmatics of focus

Modeling the Dynamic Effects of Discourse: Principles and Frameworks

International audienceWhen studying the meaning of natural language expressions, sentence level provides a natural entry point. Its relevance of course depends on the focus we want to put on the meaning: as related to thought, to communication, to truth, etc. In this paper, we concentrate on the model theoretic view on meaning, in particular via first order logic representation. More specifically, we present phenomena that illustrate the challenges raised by discourse to truth-conditional semantics and compositionality. We show that proposals to address theses challenges rely on the additional device of contexts and on the way sentences can access and modify these contexts. This capability is usually referred to as the context change potential of a sentence. Depending on the phenomenon, the contexts need to represent different kinds of information: propositions, discourse referents, and variations on these elements. We also show that taking into account the rhetorical structure of discourse leads to even richer structuring of the context. Parallel to the presentation of the phenomena, we concentrate on formalisms giving an account of the dynamics of discourse. We introduce the well established formalisms of Discourse Representation Theory (DRT) Dynamic Predicate Logic (DPL) , and the more recently developed approach based on continuation semantics. Finally, we introduce Segmented Discourse Representation Theory (SDRT) that combines the effects of dynamics and discourse structure.La phrase représente un niveau d'entrée naturel dans l'étude du sens des expressions de la langue naturelle. Sa pertinence dépend bien sûr de la perspective que l'on souhaite mettre en avant sur le sens : celle relative à la pensée, celle relative à la communication, celle relative à la valeur de vérité... Dans cet article, nous nous concentrons sur la perspective donnée au sens par la théorie des modèles, en particulier par la représentation avec la logique du premier ordre. Plus spécifiquement, nous présentons des phénomènes illustrant les difficultés posées par le discours à la sémantique vériconditionnelle et à la compositionalité. Nous montrons que les propositions pour répondre à ces difficultés reposent sur l'utilisation de contextes et de la manière dons les phrases peuvent accéder à ce contexte et le modifier. Ce mécanisme est généralement appelé potentiel de changement du contexte d'une phrase. Suivant le phénomène considéré, le contexte doit représenter différents types d'informations : des propositions, des référents de discours, et des variations de ces éléments. Nous montrons également que la prise en compte de la structure rhétorique du discours conduit à une représentation encore plus riche du contexte. Parallèlement à l'exposé de ces phénomènes, nous présentons différents formalismes qui en rendent compte. Nous présentons la théorie des représentations discursives (DRT), de la logique des prédicats dynamique (DPL), ainsi que l'approche fondée sur les continuations proposée plus récemment. Enfin nous présentons la théorie des représentations discursives segmentées (SDRT) qui combine les effets de la dynamique et de la structure discursive

The role of economic evaluation in the decision-making process of family physicians: design and methods of a qualitative embedded multiple-case study

<p>Abstract</p> <p>Background</p> <p>A considerable amount of resource allocation decisions take place daily at the point of the clinical encounter; especially in primary care, where 80 percent of health problems are managed. Ignoring economic evaluation evidence in individual clinical decision-making may have a broad impact on the efficiency of health services. To date, almost all studies on the use of economic evaluation in decision-making used a quantitative approach, and few investigated decision-making at the clinical level. An important question is whether economic evaluations affect clinical practice. The project is an intervention research study designed to understand the role of economic evaluation in the decision-making process of family physicians (FPs). The contributions of the project will be from the perspective of Pierre Bourdieu's sociological theory.</p> <p>Methods/design</p> <p>A qualitative research strategy is proposed. We will conduct an embedded multiple-case study design. Ten case studies will be performed. The FPs will be the unit of analysis. The sampling strategies will be directed towards theoretical generalization. The 10 selected cases will be intended to reflect a diversity of FPs. There will be two embedded units of analysis: FPs (micro-level of analysis) and field of family medicine (macro-level of analysis). The division of the determinants of practice/behaviour into two groups, corresponding to the macro-structural level and the micro-individual level, is the basis for Bourdieu's mode of analysis. The sources of data collection for the micro-level analysis will be 10 life history interviews with FPs, documents and observational evidence. The sources of data collection for the macro-level analysis will be documents and 9 open-ended, focused interviews with key informants from medical associations and academic institutions. The analytic induction approach to data analysis will be used. A list of codes will be generated based on both the original framework and new themes introduced by the participants. We will conduct within-case and cross-case analyses of the data.</p> <p>Discussion</p> <p>The question of the role of economic evaluation in FPs' decision-making is of great interest to scientists, health care practitioners, managers and policy-makers, as well as to consultants, industry, and society. It is believed that the proposed research approach will make an original contribution to the development of knowledge, both empirical and theoretical.</p

Complex speech-language therapy interventions for stroke-related aphasia: The RELEASE study incorporating a systematic review and individual participant data network meta-analysis

Background: People with language problems following stroke (aphasia) benefit from speech and language therapy. Optimising speech and language therapy for aphasia recovery is a research priority. Objectives: The objectives were to explore patterns and predictors of language and communication recovery, optimum speech and language therapy intervention provision, and whether or not effectiveness varies by participant subgroup or language domain. Design: This research comprised a systematic review, a meta-analysis and a network meta-analysis of individual participant data. Setting: Participant data were collected in research and clinical settings. Interventions: The intervention under investigation was speech and language therapy for aphasia after stroke. Main outcome measures: The main outcome measures were absolute changes in language scores from baseline on overall language ability, auditory comprehension, spoken language, reading comprehension, writing and functional communication. Data sources and participants: Electronic databases were systematically searched, including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Linguistic and Language Behavior Abstracts and SpeechBITE (searched from inception to 2015). The results were screened for eligibility, and published and unpublished data sets (randomised controlled trials, non-randomised controlled trials, cohort studies, case series, registries) with at least 10 individual participant data reporting aphasia duration and severity were identified. Existing collaborators and primary researchers named in identified records were invited to contribute electronic data sets. Individual participant data in the public domain were extracted. Review methods: Data on demographics, speech and language therapy interventions, outcomes and quality criteria were independently extracted by two reviewers, or available as individual participant data data sets. Meta-analysis and network meta-analysis were used to generate hypotheses. Results: We retrieved 5928 individual participant data from 174 data sets across 28 countries, comprising 75 electronic (3940 individual participant data), 47 randomised controlled trial (1778 individual participant data) and 91 speech and language therapy intervention (2746 individual participant data) data sets. The median participant age was 63 years (interquartile range 53-72 years). We identified 53 unavailable, but potentially eligible, randomised controlled trials (46 of these appeared to include speech and language therapy). Relevant individual participant data were filtered into each analysis. Statistically significant predictors of recovery included age (functional communication, individual participant data: 532, n = 14 randomised controlled trials) and sex (overall language ability, individual participant data: 482, n = 11 randomised controlled trials; functional communication, individual participant data: 532, n = 14 randomised controlled trials). Older age and being a longer time since aphasia onset predicted poorer recovery. A negative relationship between baseline severity score and change from baseline (p < 0.0001) may reflect the reduced improvement possible from high baseline scores. The frequency, duration, intensity and dosage of speech and language therapy were variously associated with auditory comprehension, naming and functional communication recovery. There were insufficient data to examine spontaneous recovery. The greatest overall gains in language ability [14.95 points (95% confidence interval 8.7 to 21.2 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.78 points (95% confidence interval 0.48 to 1.1 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with receiving speech and language therapy 4 to 5 days weekly; for auditory comprehension [5.86 points (95% confidence interval 1.6 to 10.0 points) on the Aachen Aphasia Test-Token Test], the greatest gains were associated with receiving speech and language therapy 3 to 4 days weekly. The greatest overall gains in language ability [15.9 points (95% confidence interval 8.0 to 23.6 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.77 points (95% confidence interval 0.36 to 1.2 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with speech and language therapy participation from 2 to 4 (and more than 9) hours weekly, whereas the highest auditory comprehension gains [7.3 points (95% confidence interval 4.1 to 10.5 points) on the Aachen Aphasia Test-Token Test] were associated with speech and language therapy participation in excess of 9 hours weekly (with similar gains notes for 4 hours weekly). While clinically similar gains were made alongside different speech and language therapy intensities, the greatest overall gains in language ability [18.37 points (95% confidence interval 10.58 to 26.16 points) on the Western Aphasia Battery-Aphasia Quotient] and auditory comprehension [5.23 points (95% confidence interval 1.51 to 8.95 points) on the Aachen Aphasia Test-Token Test] were associated with 20-50 hours of speech and language therapy. Network meta-analyses on naming and the duration of speech and language therapy interventions across language outcomes were unstable. Relative variance was acceptable (< 30%). Subgroups may benefit from specific interventions. Limitations: Data sets were graded as being at a low risk of bias but were predominantly based on highly selected research participants, assessments and interventions, thereby limiting generalisability. Conclusions: Frequency, intensity and dosage were associated with language gains from baseline, but varied by domain and subgroup

Communicating simply, but not too simply: Reporting of participants and speech and language interventions for aphasia after stroke

Purpose: Speech and language pathology (SLP) for aphasia is a complex intervention delivered to a heterogeneous population within diverse settings. Simplistic descriptions of participants and interventions in research hinder replication, interpretation of results, guideline and research developments through secondary data analyses. This study aimed to describe the availability of participant and intervention descriptors in existing aphasia research datasets. Method: We systematically identified aphasia research datasets containing ≥10 participants with information on time since stroke and language ability. We extracted participant and SLP intervention descriptions and considered the availability of data compared to historical and current reporting standards. We developed an extension to the Template for Intervention Description and Replication checklist to support meaningful classification and synthesis of the SLP interventions to support secondary data analysis. Result: Of 11, 314 identified records we screened 1131 full texts and received 75 dataset contributions. We extracted data from 99 additional public domain datasets. Participant age (97.1%) and sex (90.8%) were commonly available. Prior stroke (25.8%), living context (12.1%) and socio-economic status (2.3%) were rarely available. Therapy impairment target, frequency and duration were most commonly available but predominately described at group level. Home practice (46.3%) and tailoring (functional relevance 46.3%) were inconsistently available. Conclusion : Gaps in the availability of participant and intervention details were significant, hampering clinical implementation of evidence into practice and development of our field of research. Improvements in the quality and consistency of participant and intervention data reported in aphasia research are required to maximise clinical implementation, replication in research and the generation of insights from secondary data analysis

Utilising a systematic review-based approach to create a database of individual participant data for meta- and network meta-analyses: the RELEASE database of aphasia after stroke

Background: Collation of aphasia research data across settings, countries and study designs using big data principles will support analyses across different language modalities, levels of impairment, and therapy interventions in this heterogeneous population. Big data approaches in aphasia research may support vital analyses, which are unachievable within individual trial datasets. However, we lack insight into the requirements for a systematically created database, the feasibility and challenges and potential utility of the type of data collated. Aim: To report the development, preparation and establishment of an internationally agreed aphasia after stroke research database of individual participant data (IPD) to facilitate planned aphasia research analyses. Methods: Data were collated by systematically identifying existing, eligible studies in any language (≥10 IPD, data on time since stroke, and language performance) and included sourcing from relevant aphasia research networks. We invited electronic contributions and also extracted IPD from the public domain. Data were assessed for completeness, validity of value-ranges within variables, and described according to pre-defined categories of demographic data, therapy descriptions, and language domain measurements. We cleaned, clarified, imputed and standardised relevant data in collaboration with the original study investigators. We presented participant, language, stroke, and therapy data characteristics of the final database using summary statistics. Results: From 5256 screened records, 698 datasets were potentially eligible for inclusion; 174 datasets (5928 IPD) from 28 countries were included, 47/174 RCT datasets (1778 IPD) and 91/174 (2834 IPD) included a speech and language therapy (SLT) intervention. Participants’ median age was 63 years (interquartile range [53, 72]), 3407 (61.4%) were male and median recruitment time was 321 days (IQR 30, 1156) after stroke. IPD were available for aphasia severity or ability overall (n = 2699; 80 datasets), naming (n = 2886; 75 datasets), auditory comprehension (n = 2750; 71 datasets), functional communication (n = 1591; 29 datasets), reading (n = 770; 12 datasets) and writing (n = 724; 13 datasets). Information on SLT interventions were described by theoretical approach, therapy target, mode of delivery, setting and provider. Therapy regimen was described according to intensity (1882 IPD; 60 datasets), frequency (2057 IPD; 66 datasets), duration (1960 IPD; 64 datasets) and dosage (1978 IPD; 62 datasets). Discussion: Our international IPD archive demonstrates the application of big data principles in the context of aphasia research; our rigorous methodology for data acquisition and cleaning can serve as a template for the establishment of similar databases in other research areas

Predictors of Poststroke Aphasia Recovery A Systematic Review-Informed Individual Participant Data Meta-Analysis

Background and Purpose: The factors associated with recovery of language domains after stroke remain uncertain. We described recovery of overall-language-ability, auditory comprehension, naming, and functional-communication across participants’ age, sex, and aphasia chronicity in a large, multilingual, international aphasia dataset. / Methods: Individual participant data meta-analysis of systematically sourced aphasia datasets described overall-language ability using the Western Aphasia Battery Aphasia-Quotient; auditory comprehension by Aachen Aphasia Test (AAT) Token Test; naming by Boston Naming Test and functional-communication by AAT Spontaneous-Speech Communication subscale. Multivariable analyses regressed absolute score-changes from baseline across language domains onto covariates identified a priori in randomized controlled trials and all study types. Change-from-baseline scores were presented as estimates of means and 95% CIs. Heterogeneity was described using relative variance. Risk of bias was considered at dataset and meta-analysis level. / Results: Assessments at baseline (median=43.6 weeks poststroke; interquartile range [4–165.1]) and first-follow-up (median=10 weeks from baseline; interquartile range [3–26]) were available for n=943 on overall-language ability, n=1056 on auditory comprehension, n=791 on naming and n=974 on functional-communication. Younger age (<55 years, +15.4 Western Aphasia Battery Aphasia-Quotient points [CI, 10.0–20.9], +6.1 correct on AAT Token Test [CI, 3.2–8.9]; +9.3 Boston Naming Test points [CI, 4.7–13.9]; +0.8 AAT Spontaneous-Speech Communication subscale points [CI, 0.5–1.0]) and enrollment <1 month post-onset (+19.1 Western Aphasia Battery Aphasia-Quotient points [CI, 13.9–24.4]; +5.3 correct on AAT Token Test [CI, 1.7–8.8]; +11.1 Boston Naming Test points [CI, 5.7–16.5]; and +1.1 AAT Spontaneous-Speech Communication subscale point [CI, 0.7–1.4]) conferred the greatest absolute change-from-baseline across each language domain. Improvements in language scores from baseline diminished with increasing age and aphasia chronicity. Data exhibited no significant statistical heterogeneity. Risk-of-bias was low to moderate-low. / Conclusions: Earlier intervention for poststroke aphasia was crucial to maximize language recovery across a range of language domains, although recovery continued to be observed to a lesser extent beyond 6 months poststroke